Abstract 3102: Synthesis of N-benzoylamino-tetrahydropyridine analogues as selective COX-2 inhibitors and anti-breast cancer agents
Authors: Shasline Gedeon, Madhavi Gangapuram, Kinfe K. Redda, Tiffany Ardley
Journal: Cancer Research (2023)

Abstract The World Health Organization confirms breast cancer as the most common cancer globally, as of 2021, tallying 12% of new annual cancer cases. Female breast cancer is the second leading cancer in incidence rates among women after lung cancer. It is also more deadly amongst Black and Hispanic women as mortality rates increase by 40% compared to their caucasian counterparts. Hence, there is a dire need to design and develop novel molecules as effective anticancer agents. Rational design-based drug discovery has led to advancements in developing novel small molecules as effective anticancer agents. Chronic inflammation is directly related to cancer. Literature testifies to the presence and overexpression of cyclooxygenase-2 (COX-2) in various inflammation-based ailments, diseases, and many cancers. Therefore, it is imperative to investigate the relevance of cyclooxygenase-2 inhibition in cancer therapy. The tetrahydropyridine structure has been documented in several natural products. They display biological properties including antioxidant, anti-inflammatory, and chemotherapeutic. Substituted benzoylamino-5-ethyl-1,2,3,6-tetrahydropyridine analogues have been designed as COX-2 inhibitors. This project aims to synthesize thirteen novel THP analogues using a 4-step synthesis. The synthesis of these 1,2,3,6-THP analogues primarily involves the hydrolysis of ethyl-o-(mesitylenesulfonyl) acethydroxymate to render O-(mesitylsulfonyl)hydroxylamine (MSH). MSH then acts as an aminating agent as it reacts with 3-ethyl pyridine. This amination reaction affords the mesitylene salt, 1-amino-3-ethylpyridin-1-ium. Next, the salt product undergoes acylation with various substituted benzoyl chlorides to generate stable N-ylide products. Finally, the partial reduction of the ylides yields the desired final tetrahydropyridine products. Purification was completed by flash chromatography. The novel THP analogues were characterized using nuclear magnetic resonance, infrared spectroscopy, and elemental analysis. Computer-aided drug design studies provided the preliminary data constituting that the likelihood of the THP moiety generating more effective COX-2 inhibitors is dependent on suitable modifications to the structure. Further studies include testing the novel THP analogues as cyclooxygenase-2 inhibitors using COX-2 inhibition assays, and lastly, determining their anti-breast cancer activity in MDA-MD-231, MCF-7 and Ishikawa cell lines to assess their antiproliferative effects. This research was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number U54 MD007582. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Citation Format: Shasline Gedeon, Madhavi Gangapuram, Kinfe K. Redda, Tiffany Ardley. Synthesis of N-benzoylamino-tetrahydropyridine analogues as selective COX-2 inhibitors and anti-breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3102.